The integration of pharmacokinetics and pathogen susceptibility data in the design of rational dosing regimens

The integration of pharmacokinetic and pathogen susceptibility data has had an increasing impact on the design of dosage regimens. Pathogen susceptibility is often described by the minimum inhibitory concentration (MIC). While the MIC is an indicator of drug potency, it does not predict pharmacologic response in vivo when drug concentrations are fluctuating. To this end, three pharmacokinetic/pharmacodynamic (PK/PD) parameters that result from indexing pharmacokinetics to MIC have proven quite useful. A number of experimental models of infection have determined the magnitude of each parameter, AUC/MIC, Cmax/MIC and %T>MIC, required for the optimal treatment of specific pathogens. These measurements have proven to be predictive of clinical outcomes as well. As a result, PK/PD breakpoints have been determined based on the likelihood that the pharmacokinetic profile of a given dose will achieve a target PK/PD parameter value. These breakpoints correlate well with treatment success or failure, particularly evident in infections conducive to microbiologic sampling such as otitis media. Therefore, PK/PD assessments have fostered a much more targeted approach to the treatment of patients with infectious diseases, and have proven useful in the selection of antimicrobial therapy and the development of novel dosing strategies.     

Monte Carlo simulation analysis of ceftobiprole,dalbavancin, daptomycin,tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit‐isolated methicillin‐resistant Staphylococcus aureus

相似文献   

PK–PD Compass: bringing infectious diseases pharmacometrics to the patient’s bedside

Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic–pharmacodynamic (PK–PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK–PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK–PD data, patient-specific characteristics, and pathogen susceptibility data. Through the integration of these data, the application allows practitioners to assess the percent probability of PK–PD target attainment for 35 intravenous antimicrobial agents across 29 infection categories. Population PK models for each drug were identified, evaluated, and refined as needed. Susceptibility breakpoints were based upon FDA and CLSI criteria. By incorporating these data into one interface, clinicians can select the infection, pathogen, and antimicrobial agents of interest and obtain the percent probability of PK–PD target attainment for each regimen based upon patient-specific characteristics. The antimicrobial dosing regimens provided include those recommended by standard guidelines and reference texts. However, unlike these references, potential choices are prioritized based on percent probabilities of PK–PD target attainment. Such data will educate clinicians on selecting optimized antibiotic regimens through the lens of PK–PD.     

Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria

This study compared the susceptibility breakpoints based on pharmacokinetic/pharmacodynamic (PK/PD) models and Monte Carlo simulation with those defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for antibiotics used for the treatment of infections caused by Gram-positive bacteria. A secondary objective was to evaluate the probability of achieving the PK/PD target associated with the success of antimicrobial therapy. A 10000-subject Monte Carlo simulation was executed to evaluate 13 antimicrobials (47 intravenous dosing regimens). Susceptibility data were extracted from the British Society for Antimicrobial Chemotherapy database for bacteraemia isolates. The probability of target attainment and the cumulative fraction of response (CFR) were calculated. No antibiotic was predicted to be effective (CFR≥90%) against all microorganisms. The PK/PD susceptibility breakpoints were also estimated and were compared with CLSI and EUCAST breakpoints. The percentages of strains affected by breakpoint discrepancies were calculated. In the case of β-lactams, breakpoint discrepancies affected <15% of strains. However, higher differences were detected for low doses of vancomycin, daptomycin and linezolid, with PK/PD breakpoints being lower than those defined by the CLSI and EUCAST. If this occurs, an isolate will be considered susceptible based on CLSI and EUCAST breakpoints although the PK/PD analysis predicts failure, which may explain treatment failures reported in the literature. This study reinforces the idea of considering not only the antimicrobial activity but also the dosing regimen to increase the probability of clinical success of an antimicrobial treatment.     

Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation

Objectives The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters. Key findings The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two‐compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms. Conclusions A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.     

Pharmacokinetic/pharmacodynamic evaluation of antimicrobial treatments of orofacial odontogenic infections

OBJECTIVE: To evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards' (NCCLS) breakpoints. STUDY DESIGN: Retrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). METHODS: For antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters. RESULTS: Only amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints. CONCLUSION: Owing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.     

Combating resistance: application of the emerging science of pharmacokinetics and pharmacodynamics

During the last 10-15 years understanding of relationships between pharmacokinetic (PK) and pharmacodynamic (PD) parameters and bacteriological and clinical outcomes has expanded allowing correlation between in vitro potency and in vivo efficacy. PK and PD principles can be applied to development of new antibacterials and formulation of existing agents to help address the increasing prevalence of antibacterial resistance. For beta-lactams, such as penicillins, the unbound serum concentration of the drug exceeding the minimum inhibitory concentration of the causative pathogen for 40-50% of the dosing interval is predictive of bacteriologic efficacy (bacterial eradication) and can be used to determine a PK/PD breakpoint for that specific dosing regimen. Amoxicillin/clavulanate was one of the earliest antibacterials to use the unique approach of PK/PD principles to develop new and enhanced formulations, allowing it to remain a significant antibacterial agent in the management of respiratory tract infections.     

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.     

泰比培南对小鼠肺炎克雷伯菌大腿感染模型的PK/PD研究

目的：通过泰比培南对小鼠大腿克雷伯菌感染模型PK/PD研究,预测最佳PK/PD参数。方法：选用临床肺炎克雷伯菌1株,采用琼脂二倍稀释法检测药物的最低抑菌浓度（MIC）;构建小鼠的肺炎克雷伯菌大腿感染模型,分三种剂量（50、15、3 mg·kg-1）给予受试药物,观察给药24 h后大腿组织感染量变化,并采用HPLC法检测血药浓度。结果：体外测得MIC为0.03μg· mL-1;在小鼠的肺炎克雷伯菌大腿感染模型中,50、15、3 mg·kg-1三种剂量均对感染有治疗作用, PK/PD参数AUC/MIC、Cmax/MIC、T〉MIC的相关系数r2分别为0.8、0.75、0.54。结论：体内PK/PD研究表明,AUC/MIC、Cmax/MIC参数是反映泰比培南对小鼠的肺炎克雷伯菌大腿感染治疗效果主要的PK/PD参数。     

健康受试者口服氟罗沙星的药动学/药效学研究

目的:研究健康受试者口服氟罗沙星的药动学(PK)和药效学(PD),从而优化氟罗沙星的临床给药方案。方法:采用三周期自身交叉对照的方式对15名健康受试者分别口服200,300,400 mg氟罗沙星片后,以高效液相色谱法(HPLC)测定血药浓度,进而求出药动学(PK)参数。体外药效学(PD)研究是测定氟罗沙星对临床分离的15种494株常见致病菌的最低抑菌浓度(MIC)。以AUC_0-24/MIC作为氟罗沙星的PK/PD参数(靶值为100和125),采用蒙特卡洛(Monte Carlo)模拟评价氟罗沙星的3种治疗方案对不同分离菌株AUC_0-24/MIC值的药效学累积反应分数(CFR)。结果:以CFR> 90%作为抗感染经验治疗的合理选择,对于大肠杆菌和淋球菌引起的感染,或口服200 mg(qd)即可;对硝酸盐阴性杆菌、肠杆菌属和哈夫尼亚菌属引起的感染,或口服300 mg(qd)即可;对于表葡球菌、铜绿假单胞菌、志贺菌属、肺炎克雷伯杆菌、柠檬酸杆菌属、普通变形杆菌、肺炎链球菌、沙门菌属和金葡球菌(MSSA)引起的感染,或口服400 mg(qd)可获得预期满意的临床疗效并能有效预防细菌耐药性产生,而对于耐甲氧西林金葡菌(MRSA),PK/PD参数显示疗效不佳。结论:应用Monte Carlo模拟评价氟罗沙星的PK/PD参数,可以为氟罗沙星的临床最佳给药方案的制定提供参考依据。     

抗菌药的PK/PD理论及其在新抗菌药的药效研究中应用

大约在20年前发现,美国临床和实验室标准化学会发布的关于口服抗菌药的细菌药物敏感性折点,常与临床、微生物学和药代动力学结果不符。因此科学家提出了一个基于药代动力学一药效动力学(PK/PD)模型和临床结果的新方法,并以此推测细菌学转归及细菌学结果与药物敏感性的关系,并将抗菌药分为3种活性类型:①浓度依赖性杀菌和较长的持续效应,其药效依赖于给药量(AUC)或峰浓度与MIC的比值;②时间依赖杀菌却仅有低到中度的持续效应,其疗效更多地依赖于给药次数(血药浓度超过MIC的时间);③时间依赖杀菌而有较长的持续效应,其药效依赖于给药量(AUC)与MIC的比值。对此本文作了介绍。     

In-vitro pharmacokinetic/pharmacodynamic model data suggest a potential role of new formulations of posaconazole against Candida krusei but not Candida glabrata infections

Posaconazole exhibits in-vitro activity against Candida glabrata and Candida krusei. Epidemiological cut-off values set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) are 1/1 and 0.5/0.5 mg/L, respectively, but clinical breakpoints have not been established to date. This study explored the pharmacodynamics (PD) of posaconazole in a validated one-compartment in-vitro pharmacokinetic (PK)/PD model, and determined the probability of PK/PD target attainment (PTA) for the available formulations. Five C. glabrata and three C. krusei isolates with posaconazole minimum inhibitory concentrations (MICs) of 0.06–2 and 0.03–0.25 mg/L, respectively, were tested in the PK/PD model simulating different time–concentration profiles of posaconazole. The exposure–effect relationship fAUC_0–24/MIC was described for EUCAST/CLSI methods, and PTA was calculated in order to determine PK/PD susceptibility breakpoints for oral solution (400 mg q12h), and intravenous (i.v.)/tablet formulations (300 mg q24h). Fungicidal activity (~2log kill) was found against the most susceptible C. glabrata isolate alone, and against all three C. krusei isolates. The corresponding EUCAST/CLSI PK/PD targets (fAUC_0–24/MIC) were 102/79 for C. glabrata and 12/8 for C. krusei. Mean PTA was high (>95%) for C. glabrata isolates with EUCAST/CLSI MICs ≤0.03/≤0.03 mg/L for oral solution and ≤0.125/≤0.125 mg/L for i.v. and tablet formulations for the wild-type population. For C. krusei isolates, mean PTA was high (>95%) for EUCAST/CLSI MICs ≤0.25/≤0.5 mg/L for oral solution and ≤1/≤2 mg/L for i.v. and tablet formulations for the wild-type population. The use of posaconazole to treat C. glabrata infections is questionable. Intravenous and tablet formulations may be therapeutic options for the treatment of C. krusei infections, and oral exposure can be optimized with therapeutic drug monitoring (trough levels >0.6–0.9 mg/L).     

Estimation of absorption rate of α‐human atrial natriuretic peptide from the plasma profile and diuretic effect after intranasal administration to rats

The absorption rate of α‐human atrial natriuretic peptide (α‐hANP) after intranasal (i.n.) administration to rats was estimated from the plasma profile and pharmacological effect (diuretic effect) using a pharmacokinetic (PK) model and a PK–pharmacodynamic (PD) model involving data obtained after intravenous (i.v.) bolus injection. The plasma concentrations of α‐hANP after i.v. administration at different doses were fitted to a two‐compartment PK model with zero‐order excretion and input of endogenous α‐rat atrial natriuretic peptide (α‐rANP) and two elimination processes represented by Michaelis–Menten and first‐order kinetics. However, the saturable process was ignored at low doses. The plasma concentrations after low doses via the i.n. route could also be expressed by this model, but with first‐order absorption, so that an absorption rate constant was calculated using a deconvolution method. In addition, the diuretic effect plotted against the i.v. dose was represented by the Hill equation and showed an anti‐clockwise hysteresis loop versus the plasma concentration. These results suggest that the diuretic effect could be estimated by a PK–PD model having an ‘effect’ compartment or a homeostatic system. Such a PK–PD model accurately expressed the diuretic effect of α‐hANP at all doses after i.v. and i.n. administrations. The resulting absorption rate constant calculated using the PK–PD model agreed closely with that obtained by the PK model alone. The absorption rate and simulated diuretic effect suggest that, for i.n. administration of α‐hANP, a higher absorption rate constant causes a more potent diuretic effect (a dramatic effect over the early period), whereas greater bioavailability is associated with a better hypotensive effect (sustained effect). Copyright © 2001 John Wiley & Sons, Ltd.     

应用蒙特卡洛模拟优化哌拉西林他唑巴坦在血液肿瘤化疗后中性粒细胞缺乏伴发热患者中的给药方案

目的：优化哌拉西林他唑巴坦在血液肿瘤化疗后中性粒细胞缺乏伴发热（FN）患者中经验性给药方案。方法：根据哌拉西林他唑巴坦临床药动学和药效学参数,分别以50% f_T>MIC和100% f_T>MIC为目标靶值,用Crystal Ball 11.1.1.3软件对哌拉西林他唑巴坦7种给药方案（3 g q4h、3 g q6h、4 g q6h、4 g q8h,给予0.5 h输注;4 g q6h、4 g q8h,给予3 h输注;16 g持续24 h输注）进行蒙特卡洛模拟,以获得不同治疗方案的达标概率（PTA）,从而优化出最佳的抗感染方案。结果：以50% f_T>MIC为目标靶值,当MIC=16 mg·L^-1时,3 g q4h 0.5 h输注、4 g q6h 3 h输注和16 g 24 h连续输注给药方案的PTA均能达到90%以上;以100% f_T>MIC为目标靶值,当0.5≤MIC≤2 mg·L^-1时,3 g q4h 0.5 h输注、4 g q6h 3 h输注和16 g 24 h连续输注给药方案的PTA均能达到90%以上;当MIC=4 mg·L^-1和MIC=8 mg·L^-1时,仅16 g 24 h连续输注给药方案的PTA能达到90%以上。结论：对于血液肿瘤化疗后FN患者,推荐使用哌拉西林他唑巴坦4 g q6h 3 h输注或16 g 24 h连续输注的给药方案。     

Selecting antibacterials for outpatient parenteral antimicrobial therapy : pharmacokinetic-pharmacodynamic considerations

Some infectious diseases require management with parenteral therapy, although the patient may not need hospitalisation. Consequently, the administration of intravenous antimicrobials in a home or infusion clinic setting has now become commonplace. Outpatient parenteral antimicrobial therapy (OPAT) is considered safe, therapeutically effective and economical. A broad range of infections can be successfully managed with OPAT, although this form of treatment is unnecessary when oral therapy can be used. Many antimicrobials can be employed for OPAT and the choice of agent(s) and regimen should be based upon sound clinical and microbiological evidence. Assessments of cost and convenience should be made subsequent to these primary treatment outcome determinants. When designing an OPAT treatment regimen, the pharmacokinetic and pharmacodynamic characteristics of the individual agents should also be considered. Pharmacokinetics (PK) is the study of the time course of absorption, distribution, metabolism and elimination of drugs (what the body does to the drug). Clinical pharmacokinetic monitoring has been used to overcome the pharmacokinetic variability of antimicrobials and enable individualised dosing regimens that attain desirable antimicrobial serum concentrations. Pharmacodynamics (PD) is the study of the relationship between the serum concentration of a drug and the clinical response observed in a patient (what the drug does to the body). By combining pharmacokinetic properties (peak [C(max)] or trough [C(min)] serum concentrations, half-life, area under the curve) and pharmacodynamic properties (susceptibility results, minimum inhibitory concentrations [MIC] or minimum bactericidal concentrations [MBC], bactericidal or bacteriostatic killing, post-antibiotic effects), unique PK/PD parameters or indices (t > MIC, C(max)/MIC, AUC(24)/MIC) can be defined. Depending on the killing characteristics of a given class of antimicrobials (concentration-dependent or time-dependent), specific PK/PD parameters may predict in vitro bacterial eradication rates and correlate with in vivo microbiologic and clinical cures. An understanding of these principles will enable the clinician to vary dosing schemes and design individualised dosing regimens to achieve optimal PK/PD parameters and potentially improve patient outcomes. This paper will review basic principles of useful PK/PD parameters for various classes of antimicrobials as they may relate to OPAT. In summary, OPAT has become an important treatment option for the management of infectious diseases in the community setting. To optimise treatment course outcomes, pharmacokinetic and pharmacodynamic properties of the individual agents should be carefully considered when designing OPAT treatment regimens.     

Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices

The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT_>MIC) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C_max/MIC), and the ratio of the area under the 24-h concentration–time curve to MIC (AUC_0–24/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the β-lactams correlate well with the fT_>MIC. However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.     

The pharmacokinetic studies on astromicin in rats. Intramuscular, intravenous or drip intravenous administration

Absorption, tissue distribution and excretion of astromicin (ASTM) were studied in rats after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.; for 15, 30 min. or 60 min.) administration at a dose of 20 mg/kg. The pharmacokinetic studies of ASTM were carried out using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak values of ASTM observed in serum were 48.6 micrograms/ml (i.m.), 255.3 micrograms/ml (i.v.), 57.5 micrograms/ml (15 min. d.i.v.), 45.9 micrograms/ml (30 min. d.i.v.) and 39.1 micrograms/ml (60 min. d.i.v.). The pharmacokinetic parameters of ASTM after 15 min. d.i.v. administration were calculated as follows: Kel 0.110 min-1, T1/2 21.4 min., Vd beta 0.310 L/kg, Tmax 15.0 min., Cmax 58.6 micrograms/ml, AUC 1,991 micrograms X min/ml. ASTM was rapidly distributed into the kidneys and lungs. The peak values of ASTM in the kidneys were 156.8 micrograms/g (i.m.), 185.2 micrograms/g (i.v.), 132.9 micrograms/g (15 min. d.i.v.), 135.3 micrograms/g (30 min. d.i.v.) and 117.3 micrograms/g (60 min. d.i.v.). Urinary recovery rates of ASTM amounted to 85.5% (i.m.), 99.5% (i.v.) or 87.9% (30 min. d.i.v.). After i.m. or 30 min. d.i.v. administration of ASTM, no active metabolite was found in urine of rats.     

Population pharmacokinetic and pharmacodynamic model of norvancomycin

去甲万古霉素群体药代动力学与药效学研究@张菁$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @张婴元$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @施耀国$Institute of Antibiotic     

PK/PD breakpoints and clinical/bacteriological effects of cefcapene pivoxil fine granules for children at free drug concentrations in pediatric patients with respiratory infection

A post-marketing clinical study was previously conducted in pediatric patients with respiratory infection to evaluate the pharmacokinetics, efficacy and safety of cefcapene pivoxil (CFPN-PI) fine granules for children. Based on the results from this study, we evaluated PK/PD breakpoints and clinical/bacteriological effects of CFPN-PI at free drug concentrations in pediatric patients with respiratory infection to determine an effective and safe dosage regimen of CFPN-PI. The following results were obtained from 61 pediatric patients evaluated in our research. 1) The response rate of pediatric respiratory infection to CFPN-PI was 100% for laryngopharyngitis, 84.6% for acute bronchitis, 100% for tonsillitis, 100% for pneumonia and 95.8% for all. 2) The bacteriological response (eradication rate of Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, Streptococcus pneumoniae, etc.) of pediatric respiratory infection to CFPN-PI was 87.5% for laryngopharyngitis, 66.7% for acute bronchitis, 75.0% for tonsillitis, 63.6% for pneumonia and 73.8% for all. 3) The blood concentration simulation demonstrated that the PK/PD breakpoint exceeding the time above MIC (TAM) of 40% after administration of CFPN-PI 3 mg/kg three times daily was 0.27 microg/mL. 4) The pediatric patients with respiratory infection were stratified by the TAM (%) of CFPN-PI into 40% to 100% (TAM > or = 40% group) and 0% to 40% (TAM < 40% group) to compare the clinical and bacteriological effects of CFPN-PI. The clinical and bacteriological response rates, respectively, were 97.4% and 77.8% in the TAM > or = 40% group, and 88.9% and 62.5% in the TAM < 40% group. There was no difference in the clinical effect between the two TAM-stratified groups. On the other hand, the bacteriological effect, i.e., eradication rate, tended to be higher in the TAM > or = 40% group than in the TAM < 40% group, although the between-group difference was not statistically significant.     

The pharmacokinetic studies on astromicin in dogs. Intramuscular, intravenous or drip intravenous administration

The pharmacokinetics of astromicin (ASTM), a new aminoglycoside antibiotics, was studied in dogs after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.: for 0.5, 1 hr. or 2 hrs.) administration at a dose of 20 mg/kg. The pharmacokinetic parameters were calculated using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak plasma levels of ASTM were 34.1 mcg/ml (i.m.), 50.5 mcg/ml (d.i.v., 0.5 hr.), 39.8 mcg/ml (d.i.v., 1 hr.) and 28.2 mcg/ml (d.i.v., 2 hrs.), respectively. The pharmacokinetic parameters (T1/2, AUC infinity, Kel, Vd and Cl) of ASTM except Cmax and Tmax were similar for different routes of administration. Urinary recovery rates of ASTM were 90.5% (i.m.), 95.2% (i.v.), 91.6% (d.i.v., 0.5 hr.), 92.6% (d.i.v., 1 hr.) and 93.5% (d.i.v., 2 hrs.) by 24 hours. After intramuscular, intravenous or 1 hour drip intravenous administration of ASTM, no active metabolite was found in urine of dogs.